Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE Randomized Comparison of Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2 Diabetes 1 2 MATTHEW RIDDLE, MD KAREN LUTZ, PHD limit postmeal hyperglycemia. Amylin 2 2 RICHARD PENCEK, PHD KEN WILHELM, MD deficiency accelerates gastric emptying, 2 2 SUPOAT CHARENKAVANICH, PHD LISA PORTER, MD increases glucagon secretion, and alters satiety mechanisms (10,11). Pramlintide, an injectable synthetic OBJECTIVE — To compare the efficacy and safety of adding mealtime pramlintide or rapid- analog of amylin, slows gastric emptying, acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 attenuates postprandial glucagon secre- diabetes. tion, enhances satiety, and reduces food intake (12–14). Pramlintide is approved RESEARCH DESIGN AND METHODS — In a 24-week open-label, multicenter study, ␮ as adjunctive treatment for patients with 113 patients were randomly assigned 1:1 to addition of mealtime pramlintide (120 g) or a diabetes who use mealtime insulin with or titrated RAIA to basal insulin and prior oral antihyperglycemic drugs (OADs). At screening, patients were insulin naive or had been receiving Ͻ50 units/day basal insulin for Ͻ6 months. without oral antihyperglycemic drugs The basal insulin dosage was titrated from day 1, seeking fasting plasma glucose (FPG) Ն70– (OADs) and have not achieved desired Ͻ100 mg/dl. Pramlintide and an RAIA were initiated on day 1 and week 4, respectively. The glucose control. Recently, a 16-week, proportion of patients achieving A1C Յ7.0% without weight gain or severe hypoglycemia at double-blind, placebo-controlled study week 24 was the primary end point. of patients with type 2 diabetes showed that pramlintide reduces A1C and weight RESULTS — More pramlintide- than RAIA-treated patients achieved the primary end point without increasing insulin-induced hypo- (30 vs. 11%, P ϭ 0.018) with a similar dose of basal insulin. Pramlintide and an RAIA yielded glycemia when added to basal insulin Ϯ similar mean Ϯ SEM values for FPG and A1C at 24 weeks (122 Ϯ 7 vs. 123 Ϯ 5 mg/dl and 7.2 Ϯ Ϯ OADs without mealtime insulin (15). 0.2 vs. 7.0 0.1%, respectively) and similar least squares mean reductions from baseline to end Pramlintide may offer an additional point (Ϫ31 Ϯ 6 vs. Ϫ34 Ϯ 6 mg/dl and Ϫ1.1 Ϯ 0.2 vs. Ϫ1.3 Ϯ 0.2%, respectively). RAIAs but not pramlintide caused weight gain (ϩ4.7 Ϯ 0.7 vs. ϩ0.0 Ϯ 0.7 kg, P Ͻ 0.0001). Fewer patients therapeutic option for mealtime use by reported mild to moderate hypoglycemia with pramlintide than with the RAIA (55 vs. 82%), but patients with type 2 diabetes already us- more patients reported nausea (21 vs. 0%). No severe hypoglycemia occurred in either group. ing basal insulin. Rapid-acting insulin an- alogs (RAIAs) and pramlintide have CONCLUSIONS — In patients taking basal insulin and OADs, premeal fixed-dose pram- different mechanisms of action and differ- lintide improved glycemic control as effectively as titrated RAIAs. The pramlintide regimen ent patterns of desired and unwanted ef- sometimes caused nausea but no weight gain and less hypoglycemia. fects. Although both can limit after-meal hyperglycemia, RAIAs often cause weight Diabetes Care 32:1577–1582, 2009 gain and hypoglycemia (6), whereas pramlintide is associated with weight loss dding basal insulin therapy to oral Previous studies have shown that de- and nausea (15,16). This study was de- agents improves glycemic control fects in addition to insulin deficiency con- signed to compare the efficacy and side A for many patients with type 2 dia- tribute to after-meal hyperglycemia. Both effects of pramlintide versus RAIAs when betes, but up to 50% of patients continue insulin and amylin are secreted by ␤-cells, added to basal insulin to intensify treat- to have A1C values Ͼ7% (1–5). Persistent and, in individuals with abnormal ␤-cell ment of type 2 diabetes. after-meal hyperglycemia is generally ob- function, glucose- and mixed meal– served in such patients (6). The usual next stimulated secretion of both hormones is RESEARCH DESIGN AND step in treatment is addition of mealtime delayed and reduced (7–9). Insulin defi- METHODS — Patients enrolled were insulin injections, but this approach in- ciency impairs suppression of hepatic aged 18–75 years, had a clinical diagnosis creases risks of weight gain and hypogly- glucose production and enhancement of of type 2 diabetes, and had A1C Ͼ7% and cemia (4,6). glucose uptake by tissues that normally Յ10% with or without use of any combi- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● nation of metformin, thiazolidinedione, From the 1Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine, Oregon or sulfonylurea OADs. Study participants 2 Health & Science University, Portland, Oregon; and Amylin Pharmaceuticals, San Diego, California. were pramlintide naive and either insulin Corresponding author: Ken Wilhelm, [email protected]. naive or had used Ͻ50 units/day of basal Received 2 March 2009 and accepted 23 May 2009. Ͻ Published ahead of print at http://care.diabetesjournals.org on 5 June 2009. DOI: 10.2337/dc09-0395. insulin for 6 months. Inclusion criteria Clinical trial reg. no. NCT00467649, clinicaltrials.gov. included BMI Ն25 and Յ50 kg/m2. Fe- © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly male patients were neither pregnant nor lac- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. tating and were postmenopausal or using org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby birth control. Candidates were excluded if marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. they adhered poorly to diabetes manage- DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009 1577 Pramlintide versus mealtime insulin ment recommendations, had recurrent nificant nausea. Patients randomly as- signed patients receiving at least one dose severe hypoglycemia within the last 6 signed to an RAIA received only titrated of study medication. Missing individual months, or had a history of hypoglycemia basal insulin therapy for 4 weeks to avoid data were imputed from the last sched- unawareness. Patients with gastroparesis the hypoglycemia risk associated with titrat- uled visit (last observation carried for- or those who required medications to al- ing basal insulin and an RAIA simulta- ward). Insulin dose was analyzed in the ter gastric motility were excluded, as were neously. After 4 weeks, RAIA-randomized ITT observed population. Measured val- patients using exenatide or sitagliptin, patients started RAIA therapy with 5 units ues for insulin dose, A1C, FPG, and any antiobesity agents, systemic glu- of lispro, aspart, or glulisine before each glucose increments are presented as arith- cocorticoid agents, or investigational meal. Mealtime insulin doses were ad- metic mean Ϯ SEM. medications. Patients with eating disor- justed with investigator guidance by 1–2 Fisher’s exact test was used to com- ders, a history of bariatric surgery, or plans units every 3–7 days with the aim of pare the proportion of patients achieving to lose weight were excluded, as were pa- maintaining glucose concentrations at the primary end point. The Cochran- tients with any significant medical condi- Ն70 and Ͻ100 mg/dl before the subse- Mantel-Haenszel test that controlled for tions or advanced diabetes complications. quent meal or (for the dinnertime dose) at A1C at screening was used as a confirma- bedtime. Patients self-monitored blood tory test. Intergroup comparisons of con- Ethical considerations glucose daily according to individualized tinuous changes from baseline were The study protocol was approved by ap- advice from site investigators. A seven- assessed with ANOVA models including plicable institutional review boards and point glucose profile consisting of mea- treatment group, A1C at screening conducted in accordance with the Decla- surements taken 15 min before and 1.5–2 (Յ9.0% or Ͼ9.0%), insulin treatment be- ration of Helsinki. All patients provided h after the start of each of the three meals fore screening, and baseline value (for pa- written informed consent before study and at bedtime was completed during the rameters other than A1C). Data were initiation. week before each visit. At each visit, reported as least squares mean change Ϯ weight, body circumference, and vital SEM. Study design and interventions signs were measured and blood glucose This was a randomized, open-label, par- values were reviewed. Participants were RESULTS allel-group, multicenter 24-week study counseled on adjustment of basal and conducted at 29 centers throughout the mealtime insulin dosage (RAIA group) at Patient disposition, baseline U.S. between April 2007 and May 2008 (a each visit. A1C was measured at all study demographics, and therapies complete list of the participating investi- visits, and FPG was measured at screen- Of 113 patients randomly assigned, 48 gators can be found in the APPENDIX). After ing, baseline, and weeks 4, 12, and 24. No (84%) pramlintide-treated and 50 (89%) the screening visit, eligible patients visited specific lifestyle modification was ad- RAIA-treated patients completed the the study center on day 1 (baseline) and at vised; patients were asked to maintain study (Table 1). One patient in the pram- weeks 4, 8, 12, 18, and 24. Scheduled usual diet and exercise patterns. lintide group withdrew consent before in- telephone visits to review self-monitored jecting study medication, resulting in an glucose measurements and direct insulin Study end points ITT population of 56 patients per treat- adjustment occurred between visits. Ran- The primary end point was the propor- ment group.